P3.42. BRAIN TSUNAMIS – MODELING MIGRAINE-LINKED SPREADING DEPOLARIZATION
AND THE EFFECT OF VALPROATE
Emilia Goszczyńska1,2,3, Brett C. Carter2
1 International Max Planck Research School for Neurosciences, 3 Hermann-Rein St., Göttingen, Germany
2 European Neuroscience Institute Göttingen, Department of Synaptic Physiology and Plasticity, 5 Grisebach St., Göttingen, Germany
3 University of Göttingen, Wilhelmsplatz 1, Göttingen, Germany
INTRODUCTION: Migraine is a common chronic neurological disorder, affecting nearly 15% of the global population. It is marked by recurrent headaches, often arising with migraine aura (visual disturbances, sensory changes and speech or language difficulties) before the headache. Cortical spreading depression or depolarization (CSD) is considered to be an underlying mechanism of the migraine aura. It presents as waves of abrupt and sustained mass depolarization in neurons that propagates across the cortex.
AIM(S): This project aimed to induce CSD in acute mouse brain slices as a model to study the pathology underlying migraine aura. Moreover, the effect of valproate, used clinically as a preventive anti-migraine drug, was studied on the course of CSD, in order to examine the mechanism of action of the drug.
METHOD(S): High-concentration KCl puffs of increasing duration were applied to cortical layer 2/3 in acute mouse brain slices to induce CSD. Simultaneously, the membrane potential of a nearby pyramidal neuron was recorded (whole-cell current-clamp) as well as an intrinsic optical signal. CSD was observed as a spreading wave in the optical signal and a long-lasting depolarization in neurons. Recordings in valproate and control conditions were compared to access differences in CSD course and the mechanism of action of the drug.
RESULTS: CSD can be induced ex vivo in acute mouse brain slices and used as a therapeutic target for migraine prophylactic drugs. Valproate did not inhibit CSD initiation or the duration of the depolarization at half amplitude. Although it decreased the peak amplitude of depolarization of neurons during CSD, the acute treatment was ineffective to prevent CSD.
CONCLUSIONS: Pharmacological modulation of CSD could help in diminishing neurological conditions such as migraine with aura. Mechanisms of CSD initiation and treatment options can be studied ex vivo in acute mouse brain slices. Although valproate acute treatment did not prevent CSD, it may be effective in migraine prophylaxis during chronic use.
FINANCIAL SUPPORT: ERC starting grant 802354 "NovelNMDA"